Sickle cell disease (SCD) is caused by homozygosity for a single mutation of the beta hemoglobin gene. Despite the constancy of this genetic abnormality, the clinical course of patients with SCD is remarkably variable. SCD can affect the function and cause the failure of multiple organ systems through the process of vaso-occlusion. However, we as yet do not understand why the clinical course of SCD and the organs affected are so variable among patients. The process of vaso-occlusion itself appears both complex, involving multiple pathophysiological processes, as well as possibly variable from one organ system to another. This study, therefore, is designed to identify genetic factors that predispose SCD patients to develop specific end-organ complications and to experience more or less severe clinical courses. We will0 enroll 1000 patients with Hb SS and Hb S-beta thalassemia being followed at three regional institutions (Duke University Medical Center, University of North Carolina Medical Center, and Emory University Medical Center). Medical information obtained will identify the presence or absence of specific targeted outcomes (overall disease severity as well as specific types of end organ damage). All clinical data will be managed and stored on the PEDIGENE system and will include medical status (history, physical examination, and laboratory results) and information regarding potentially confounding environmental factors. We will also obtain blood for DNA analysis, and plasma samples potentially useful for later correlative studies (e.g. of cytokine levels or coagulation activation) will also be stored. Information on sample quality and quantity will be stored in the PEDIGENE system and linked to the clinical data obtained. Identification and development of SNPs for the candidate target genes will be performed, and the DNA samples will be analyzed for these, with results entered into the PEDIGENE system. State-of-the-art statistical methods will be used to examine the relationship between specific clinical outcomes with the SNPs, to determine which genetic characteristics predispose patients with SCD to a more or less severe overall clinical course as well as to individual organ-specific complications. Identification of such genetic factors will reveal new targets for development of therapy individualized to specific complications of SCD, thus leading eventually to improved outcomes and increased life expectancy for patients with SCD.